During open-heart surgery, the myocardium is subjected to varying periods of global ischemia. The resulting ischemia - reperfusion injury contributes to postoperative cardiac dysfunction, especially in the elderly. Indeed, the aged myocardium is highly vulnerable to metabolic injury and demonstrates a deficient capacity to restore cellular energetics and ionic balance on reperfusion. Although the subcellular mechanisms underlying the reduced tolerance of the senescent heart to metabolic stress are not fully understood, mitochondrial Ca2+ overload and associated energetic failure have been proposed to play a significant role in myocardial dysfunction in the elderly. However, measures to prevent mitochondrial dysfunction in the senescent myocardium are lacking. Our preliminary results indicate that modulation of the activity of a metabolic sensor, recognized as the mitochondrial ATP-sensitive K+ (mitoKATP) channel, effectively prevents mitochondrial Ca2+ overload, and preserves mitochondrial functional and structural integrity under metabolic stress. Therefore, we here hypothesize that activation of mitoKATP channels by pharmacological and/or genetic means could provide a strategy for enhanced tolerance of the senescent myocardium to ischemic stress. The specific aims of this proposal are: I) to define the protective potential of mitoKA1-P channel openers in the preservation of the senescent myocardium, ii) to determine the mechanisms underlying mitochondria-dependent protection of the senescent mitochondria, and iii) to engineer stress-tolerant cardiac cells through mitochondrial over-expression of KATP channel genes. The proposed specific aims will be tested in adult and senescent isolated mitochondria, and wild type and genetically engineered cardiac cells and then translated to the whole organ level. The significance of this proposal is in establishing a novel principle of myopreservation of the senescent heart by targeting protection of mitochondrial homeostasis and associated energetic pathways. This is especially relevant for cardiac surgery in the elderly, with the ultimate goal of limiting post-bypass pump failure.